Infection with hepatitis B virus is a major cause of liver disease worldwide and accounts for 5-10 per cent of chronic liver disease and cirrhosis in the United States. Safe and effective vaccines are now available for prevention of hepatitis B. However, therapies for the disease once it has occurred are unsatisfactory. Alpha interferon was the first antiviral agent shown to be effective in this disease and was licensed for this indication in the United States in 1993. The basis for licensure were, in part, studies conducted in the Liver Diseases Section of NIH. However, alpha interferon is effective in only one-third of patients with typical chronic hepatitis B and its role in atypical forms of this disease remain unclear. Current activities in the Liver Diseases Section are focused on developing better therapies to prevent longterm consequences. A trial of the combination of alpha interferon and the nucleoside analogue famciclovir is underway. This combination results in an additive decrease in serum levels of HBV DNA but no increase in longterm clearance of hepatitis B has been found. A pilot study of lamivudine for typical and atypical forms of chronic hepatitis B is being conducted. Virtually all patients with chronic hepatitis B have had a serum biochemical, virological and histological response to lamivudine in a dose of 100 mg once daily. However, breakthrough with viral resistance has occurred in 20 percent of patients. Longterm safety and benefit of lamivudine are now being evaluated. Patients with viral resistance will be evaluated using new antivirals (adefovir, famciclovir, lobucavir) alone or in combination with lamivudine. A multicenter trial of the combination of lamivudine and famciclovir is being planned.